A number of iodothyronines are present in blood, which are directly produced by thyroid gland or are the result of peripheral metabolism of other iodothyronines. Among them, 3,5,3′-triiodothyronine (acronym T3) is deemed to be the biological active form of thyroid hormone (TH), because it has shown high affinity for the specific receptors of the same and is normally present in serum at a concentration sufficient for the activation of said receptors.
The main secretion product of thyroid gland in the healthy adult is thyroxine, commonly designated with the acronym T4. It is peripherically converted to its biologically active form, T3 (Ref. 1), through enzymatic removal of an iodine atom from the external aromatic ring of the molecule by both type I and type II 5′-iodothyronine monodeiodinases (type I MD and type II MD, respectively). This metabolic pathway is the main mechanism of endogenous production of T3; on consequence, T4 can properly be considered a pro-hormone. On the other hand, a minor part of T3 is also directly secreted by thyroid. On average, the amount of T4 produced in an adult being of 70 Kg weight every day amounts to 100 μg, while the total production of T3 amounts to around 25 μg. 4-8 μg of T3 out of said 25 μg are directly secreted by thyroid and the remaining ones derive from the peripheral conversion of T4.
T3 undergoes two different metabolic pathways. The main metabolic pathway consists in the partial deiodination of the inner aromatic ring by type III 5-iodothyronine monodeiodinase (type III MD) to give 3,3′-diiodothyronine, which is biologically non-active and is further metabolized through deiodination or sulfoconjugation. The other metabolic pathway regards around 20% of the total amount of T3 produced by the body and brings on sulfoconjugation of T3 to give T3S, which is not able to bond to the thyroid hormones (Ref. 2), thus resulting biologically non-active (Ref. 3).
Contrary to what happens with T3, T3S is not deiodinated by type III MD. Rather, it resulted to be an excellent substrate for type I MD (Ref. 4), which converts it very quickly into 3,3′-diiodothyronine sulphate. On consequence it has been widespread common knowledge that, in the healthy adult being, sulfoconjugation of T3 to give T3S represents a way for speeding up the catabolism of T3, so facilitating its biliary and urinary excretion. Actually, it was found that serum levels of T3S, physiologically low in the health adult, are higher when type I MD activity is reduced.
Yet, it has also unexpectedly been found that, just in some body districts and organs, sulfatases exist which, under particular physiological conditions and situations, are able to convert again T3S into its active form T3 (Ref's. 7-9).
Such enzymes have been described in the intestinal microflora as well as in body tissues like liver, kidneys and nervous central system (Ref. 10).
Recently, it has been found that endogenous T3S levels in serum are quite high during intrauterine life and as such are kept by the body, i.e. higher than the ones normally found in the adult being, at least until the forth month of postnatal life (Ref. 11). Considering the essential role played by thyroid hormones during growth, in particular as far as nervous central system functions are involved, suppositions have been made about the possibility that, in this tissue, T3S may also possibly be used by the body as an occasional source of T3, if and when needed, during the first period of life. Studies performed on autoptic specimens of human nervous cerebral tissue post-mortem showed that the amount of T3 in the same results limited by type III MD (Ref. 12). While this enzyme does not attack T3S, it has been surmised that T3S may exceptionally represent an alternative endogenous source of T3 hormone in those tissues which contain sulfatases able to reconvert T3S into its active form, just in case a particular need of the hormone arises in said tissues (Ref's. 8, 13).
Further studies have been performed to ascertain the effective role played by T3S during production and metabolism of thyroid hormones. Said studies have recently demonstrated that it shows thyromimetic effects in hypothyroid rats (Ref. 10) as well as in euthyroid rats (Ref. 14). In both cases T3S has shown a potency of around one fifth that of T3. Moreover both treatments with T3S and with T3 produced a significant reduction of serum levels of thyreotropic hormone (TSH) in euthyroid rats, thus showing to possess similar capability in inhibiting its secretion. On the contrary, in the case of hypothyroid rats, T3S showed a poor capability of inhibiting TSH secretion when compared to T3. It is well known that TSB is a highly responsive indicator to the functional status of thyroid gland and consents to detect the smallest alterations of its hormonal secretion. Actually, its levels are higher under conditions of reduced thyroid functionality, even in those conditions that are defined as sub-clinical, while they are reduced when an excess of thyroid hormones are present. Accordingly, T3S seems unexpectedly non-comparable to T3 as far as its capability of inhibition on formation of TSH is involved.
In conclusion, particularly in view of the latest studies, a clear and complete knowledge of the biological role played by T3S has not yet been reached.
In fact its main, well-grounded and universally accepted, feature is its non-biological activity, i.e. it is a biologically inert metabolite of T3 (Ref's. 2 and 3), and the sulfation pathway is regarded as a metabolic activator of T3 catabolism (Ref. 5).
On the other hand, only in particular tissues and under exceptional critical conditions due to shortage of thyroid hormone in those tissues, it has been shown its potential as an endogenous local source of T3.
As a result, today the skilled technician is still facing a complex, somewhat conflicting, situation, which highlights only some of the biological characteristics of the product and needs more exhaustive in depth studies.
In any case, none of the several documents forming the state-of-the-art discloses, shows or suggests the possibility of using this anomalous metabolite of T3 in therapy. No close prior-art document, either of experimental nature or substantially speculative, either taken alone or in combination with other related documents, suggests the use, or even the potential use of T3S as a medicament, taken as such or preferably in combination with other thyroid hormones or pro-hormones, like, for example T4. The fact that, only in some specific tissues of the body and under particular, peculiar circumstances, part of T3S can be reconverted into T3 does not mean, nor implies, nor suggests that it is possible to generalize this feature to the whole organism through exogenous administration of the product. In particular, there is no suggestion that oral administration of the product, even in protected form according to known methods of the pharmaceutical technique, may render it bioavailable also because it is well known that in those districts where suitable sulfatases are not present the same is rapidly metabolized and excreted through the bile and urines.